The present invention relates to phenidate drug compositions for treating certain Central Nervous System disorders such as Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), HIV/AIDS cognitive decline, and AIDS Dementia Complex. This invention features such drugs having decreased side effects, reduced euphoric effect, and reduced drug abuse potential.
Attention Deficit Disorder (ADD) is the most commonly diagnosed nervous system illness in children. Patrick et al., J. Phamacol. and Exp. Therap., 241:152-158 (1987). Symptoms of ADD include distractibility and impulsivity. A related disorder, termed Attention Deficit Hyperactivity Disorder (ADHD), is further characterized by increased symptoms of hyperactivity in patients. Racemic methylphenidate (e.g., Ritalin(copyright) ) is a mild Central Nervcus System stimulant with pharmacological activity qualitatively similar to amphetamines, and has long been the drug of choice for symptomatic treatment of ADD in children. Graenhill, L., Child and Adol. Psych. Clin. N.A., Vol. 4, Number 1:123-165 (1995).
Current administration of racemic methylphenidate, however, often results in notable aide effects such as anorexia, weight loss, insomnia, dizziness and dysphoria. Additionally, racemic methylphenidate, which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for substance abuse in patients.
At least 70% of HIV-infected individuals who have developed Acquired Immunodeficiency Syndrome (AIDS) eventually manifest cognitive defects, and many display signs and symptoms of dementia. See Navia at al., Annals of Neurology, 19:517-524 (1986). Complaints of forgetfulness, loss of concentration, fatigue, depression, loss of attentiveness, mood swings, and thought disturbance are common in patients with Human Immunodeficiency Virus (HIV) disease. Douzenis et al., Proc. 7th int""l. Conf. AIDS, 1, MB, 2135:215 (1991); Holmes et al., J. Clin. Psychiatry, 50:5-8 (1989). Racemic methylphenidate has been used to treat cognitive decline in AIDS/ARC patients. Brown, G., Intl. J. Psych. Med. 25(1): 21-37 (1995). As described above, racemic methylphenidate, a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for drug abuse.
U.S. Pat. No. 2,507,631, to Hartmann et al. describes methylphenidate and processes for making the same. U.S. Pat. No. 2,957,880, to Rometsch et al. describes the conversion of xcex1-aryl-xcex1-piperidyl-(2)-acetic acids and derivatives thereof (including methylphenidate) into their respective racemates. Each of these patents is incorporated herein by reference.
Holmes et al., J. Clin. Psychiatry, 50:5-8 (1989) reported on the use of racemic methylphenidate (Ritalin(copyright)) and dextroamphetamines in the treatment of cognitive impairment in AIDS patients.
Srinivas et al., J. Pharmacol. and Exp Therap., 241:300306 (1987) described use of racemic dl-threo-methylphenidate (Ritalin(copyright)) in the treatment of ADD in children. This study noted a 5-fold increase in plasma levels of d-threo-methylphenidate in children treated with racemic methylphenidate, but was otherwise inconclusive with regard to the efficacy of a single methylphenidate isomer at therapeutically significant doses.
Srinivas et: al., Clin. Pharmacol. Ther., 52:561-568 (1992) studied the administration of dl-threo, d-threo and 1-threo-methylphenidate to children suffering from ADHD. While Srinivas et al. reported the pharmacodynamic activity of dl-threo-methylphenidate resides in the d-threo isomer, this study investigated neither the adverse side effects of the 1-threo isomer, nor the euphoric effects of the single isomers or racemate. Single isomer dosages below xc2xd of the racemate dosage were not studied.
Patrick et al., J. Pharmacol. and Exp. Therap., 241:152158 (1986) examined the pharmacology of the enantiomers of threo-methylphenidate, and assessed the relative contribution of each isomer to central and peripheral actions of Ritalin(copyright).
Brown, G., Intl. J. Psych. Med., 25 (1) :21-37 (1995) reported the use of racemic methylphenidate for the treatment of AIDS"" cognitive decline.
Patrick et al., Psychopharmacology: The Third Generation of Progress, Raven Press, N.Y. (1987) examined the pharmacokinetics and actions of methylphenidate in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Patrick noted the d-threo isomer possesses higher activity than the 1-threo isomer, and that d-threo methylphenidate may be responsible for the therapeutic activity in the racemic drug.
Aoyama et al., Clin. Pharmacol. Ther., 55:270-276 (1994) reported on the use of (+)-threo-methylphenidate in the treatment of hypersomnia. Aoyama et al. describe a correlation between sleep latency in patients and plasma concentration of (+)-threo-methylphenidate.
Glutathione is an important antioxidative agent that protects the body against electrophilic reactive compounds and intracellular oxidants. It has been postulated that HIV-AIDS patients suffer from drug hypersensitivity due to drug overload and an acquired glutathione deficiency. See Uetrecht et al., Pharmacol. Res., 6:265-273 (1989). Patients with HIV infection have demonstrated a reduced concentration of glutathione in plasma, cells and broncho-alveolar lavage fluid. Staal et al., Lancet, 339:909-912 (1992). Clinical data suggests that HIV-seropositive individuals display adverse reactions to the simultaneous administration of several otherwise therapeutic drugs. Rieder et al., Ann. Intern. Med., 110:286-289 (1989). It is desirable to provide for the administration of methylphenidate in reduced dosages among patients with drug hypersensitivity due to HIV infection.
There is a long-felt and very intense need for phenidate drug compositions, especially methyl phenidate, which are less susceptible to unlawful abuse and which exhibit diminished side effects while retaining therapeutic efficacy.
Phenidate drugs in accordance with this invention have the structure: 
where R1 is C1-C4 alkyl and R2 is either C1-C4 alkyl or hydrogen. Of this family of drugs, methylphenidate, where R1 is methyl and R2 is hydrogen, is the most well known, having long been prescribed under the trade mark Ritalin(copyright). Phenidate drugs are xcex1-aryl-xcex1-piperidyl-2-acetic acids and comprise two centers of asymmetry, existing as four separate optical isomers as follows: 
It is known that certain physiological properties of methylphenidate and other phenidate drugs are dependent upon stereochemistry. Thus, while the threo racemate of methylphenidate is understood to produce the desired central nervous system action, the erythro racemate is thought to contribute to hypertensive side effects.
It is now believed, however, that another stereochemical distinction also applies. Studies in animals, children and adults have demonstrated pharmacological activity in the D-threo isomer of methylphenidate (2R,2xe2x80x2R). See Patrick et al., J. Pharmacol. and Exp. Therap., 241:152-158 (1987). The role of the L-threo isomer in toxicity or adverse side effects has not been examined heretofore although the potential for isomer ballast in methylphenidate and other phenidate drugs is of concern for many patient groups, particularly those drug hypersensitive patients as described above.
Although L-threo-methylphenidate is rapidly and stereoselectively metabolized upon oral administration by extensive first pass metabolism, intravenous administration or inhalation results in high L-threo methylphenidate serum levels. Srinivas et al., Pharmacol. Res., 10:14-21 (1993). Intravenous administration and inhalation are methods of choice by drug abusers of current, racemic methylphenidate formulations. It is now believed that the euphoric effect produced by current formulations of methylphenidate is due to the action of L-threo-methylphenidate, rather than the pharmaceutically efficacious D-threo compound.
Accordingly, it has now been discovered that the incorporation into pharmaceutical formulations of the D-threo isomer (2R,2xe2x80x2R) of a phenidate drug, especially methylphenidate, with the substantial exclusion of the other three isomers of the phenidate, especially the L-threo isomer, produces a phenidate medication dosage form which retains high pharmaceutical efficacy levels upon administration to patients, while simultaneously possessing fewer or reduced side-effects, reduced euphoric effect and reduced potential for abuse.
Patients suffering from Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, AIDS cognitive decline, and AIDS Dementia Complex are benefitted by receiving phenidate drug, especially the preferred methylphenidate, in a dosage form which substantially excludes three of the four stereoisomers, D erythro, Lerythro, and L-threo. Stated alternatively, such dosage forms comprise D-threo phenidate in the substantial absence of L-threo and both erythro stereoisomers.
The present invention also provides dosage forms of phenidate drugs for treating Attention Deficit Disorder and Attention Deficit Hyperactivity Disorder in children and adults while providing for reduced side effects, reduced euphoric effect and reduced potential for abuse. This is accomplished by formulating dosage forms for administration to patients comprising D-threo-phenidate or a pharmaceutically acceptable salt thereof, substantially free of the L-threo isomer and both erythro isomers. The invention further provides methods of treating AIDS-related dementia and related cognitive disorders while providing for reduced side effects, reduced euphoric effect, and reduced abuse potential comprising administering D-threo-phenidate (2R,2xe2x80x2R) of the formula: 
or a pharmaceutically acceptable salt thereof, substantially free of the other three stereoisomeric forms of the drug.
In accordance with the invention, R1 is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl. It is preferred that R1 be methyl. R2 may be hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl and may appear either ortho, meta or para to the acetic acid moiety. Additional substitutients may also appear in the phenidate drug molecule, either in the aryl ring, in the pipiridine heterocycle of in the ester function, however, extensive substitution is not preferred.
Salts of phenidates, such as the conventional hydrochloride salts, are also within the spirit of the invention and all such salts are specifically contemplated hereby.
Preferably, R1 is methyl and R2 is hydrogen such that the phenidate drug is methylphenidate.
Prescription of methylphenidate to treat AIDS cognitive decline and AIDS Dementia Complex associated with HIV infection is becoming increasingly popular. However, high doses in excess of 40 mg/day are not well tolerated by a substantial number of HIV-infected patients when treated over weeks or months. Brown, G., Int""l J. Psychiatry. Med., 25:21-37 (1995). The exclusive D-threo isomer formulations of the present invention enable a lowered dosing therapy with avoidance of the administration of the stereoisomer believed to be responsible for adverse side effects and abuse potential resulting in improved efficacy for diseased patients and particularly HIV-infected patients.
Racemic methylphenidate and its individual isomers are known. See U.S. Pat. Nos. 2,507,631 and 2,957,880. They can be prepared by conventional techniques, and can be obtained from a variety of commercial sources. Moreover, the D-threo-isomer of methylphenidate and other phenidate drugs can be prepared in accordance with Ser. No. 08/583,317 filed Jan. 5, 1996, which application forms a parent to this application and has been incorporated herein by reference. Examples forming part of this application set forth certain preferred synthetic routes to the phenidate compounds useful in the practice of this invention. Persons of ordinary skill will be able to modify such procedures to prepare the lower alkyl substituted phenyl derivatives and lower alkyl esters contemplated herein without undue experimentation. Thus, preparation of ethyl, propyl, isopropyl etc. esters is a simple matter in view of the synthetic schemes set forth. Likewise, substituting the phenyl ring with one or more alkyl or other substituients may also be accomplished.
The dosage forms of the present invention can be administered orally, rectally, parenterally, or transdermally, alone or in combination with other psychostimulants, antidepressants, and the like to a patient in need of treatment. Oral dosage forms include tablets, capsules, dragees, and other conventional, pharmaceutical forms. Isotonic saline solutions, conveniently containing about 1-40 milligrams of drug per milliliter can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes. Rectal administration can conveniently be effected through the use of suppositories such as can easily be formulated from conventional carriers such as cocoa butter. Transdermal administration can be effected through the use of transdermal patch delivery systems and the like. The preferred routes of administration are oral and parenteral.
The dosage employed should be carefully titrated to the patient, considering age, weight, severity of the condition, and clinical-profile. Typically, the amount of d-threo-methylphenidate administered will be in the range of 1-50 mg/day, but the actual decision as to dosage will depend upon the exact phenidate drug being employed and will be made by the attending physician as a matter of routine. Such physician can, however, determine an appropriate regime employing well-known medical considerations. Such persons will appreciate that the overall dosage amount will be significantly smaller than that used with the corresponding racemic drug, since the undesired enantiomers are not included in the present dosage forms.
Accordingly, a pharmaceutically effective amount of a phenidate drug in accordance with this invention will be understood by persons of ordinary skill in the art to be that amount of the selected D-threo phenidate which, upon administration to a patient, would result in a sensible and therapeutically useful effect.
When phenidates other than methylphenidate are to be administered, it will be appreciated that the effective amount of drug will likely be different than for methylphenidate. Determination of such amount, however, is well within the routine skill of the practitioner. In accordance with preferred embodiments, from 1 to about 50 mg will be administered to patients, with from about 2 to about 20 mg per day being still more preferred. In still more preferred embodiments, patients will receive from about 2xc2xd to about 12 mg per day.
It is desirable to provide unit dosage forms for administration of compounds of the invention comprising from about 1 to about 50 mg of drug, with amounts of from about 2 to about 20 and particularly from about 2xc2xd to about 12 mg being still more preferred. Oral administration is the protocol of choice, however other routes of administration, such as intravenous, intraperitoneal, rectal and the like may also be employed in formulating the unit dosage forms of this invention. Carriers, diluents and excipients are conventionally employed in formulating unit dosage forms and the same are selected as a matter of routine depending upon the selected route of administration. For oral administration, formulation into tablets using tabletting excipients are conveniently employed, although capsular and other oral forms are also useful.
The present invention provides enhanced relief for patients suffering from Attention Deficit Disorder and Attention Deficit Hyperactivity Disorder while providing for reduced side effects, reduced euphoric effect, and reduced abuse potential through administration of D-threo-methyl-phenidate substantially free of the L-threo and other isomers. The invention gives rise to methods of treatment of AIDS related dementia and related cognitive disorders with D-threo-methylphenidate substantially free of the remaining isomers.
The term, xe2x80x9csubstantially free as it applies to a stereoisomer in accordance with a composition of this invention means that the composition contains no more than 10% by weight of the isomer in question. It is preferred that such composition have less than about 2% of the unwanted isomers and even more preferred that less than 1% be present. When applied to a plurality of stereoisomers, then all of the isomers, taken together, comprise no more than 10% by weight of the composition and preferrably less than 2%. It is preferred that compositions characterized as being xe2x80x9csubstantially freexe2x80x9d of all stereoisomers but the D-threo isomer comprise no more than about 5% of other isomers. It is still more preferred that no more than 1% of the undesired isomers be present.
The following examples will serve to further typify the nature of the invention, but should not be construed as a limitation on the scope thereof, which is defined solely by the appended claims.